Targeting myeloid cells for regulation of alum-based immunity

靶向骨髓细胞调节明矾免疫

• 批准号: 10546495
• 负责人: Prosper N Boyaka
• 金额: $ 59.38万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-01-01 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10546495
• 关键词: Address; Adjuvant; Affect; Affinity; Animal Model; Antibodies; Antibody Formation; Antibody Response; Antigen-Presenting Cells; Antigens; B-Lymphocytes; Binding; Blood; Blood Circulation; Cells; Data; Dendritic Cells; Development; Dose; Ebola; Edema; Elastases; Enteral; Enzymes; Epithelial Cells; Family; Family suidae; Fees; Future; Genes; Germ; Germ-Free; Goals; Growth Factor; Human; Immune; Immune response; Immunity; Immunization; Immunoglobulin A; Immunoglobulin Class Switching; Immunoglobulin G; Immunoglobulin Isotypes; Immunoglobulin Switch Recombination; Infection; Infectious Agent; Injections; Kinetics; Leukocyte Elastase; Licensing; Measures; Memory B-Lymphocyte; Modeling; Mucosal Immune Responses; Mucosal Immunity; Mucous Membrane; Mus; Myeloid Cells; Neutrophil Infiltration; Nose; Oral; Outcome Assessment; Pathway interactions; Play; Predisposition; Prevention; Production; Rectum; Regulation; Research; Role; Rotavirus; Rotavirus Infections; Route; Secretory Immunoglobulin A; Seminal; Serine Protease; Serum; Signal Pathway; Signal Transduction; Site; Specificity; Subunit Vaccines; Supplementation; Surface; Symptoms; T cell response; Testing; Toxin; Transcript; Tretinoin; Vaccine Adjuvant; Vaccines; Virus; Vitamins; Wild Type Mouse; Work; ZIKA; aluminum sulfate; chemokine; cytokine; efficacy evaluation; enteric virus infection; germ free condition; improved; in vivo; innovation; mucosa-associated lymphoid tissue; mucosal vaccine; neutrophil; neutrophil elastase inhibitor; novel; oral vaccine; pathogen; pharmacologic; prevent; protective effect; rectal; response; stem; transcriptome sequencing; vaccine delivery

Alum is the most widely used adjuvant in current subunit vaccines against infectious agents. Mucosal tissues represent the main portal of entry of pathogens. In contrast with the general bloodstream in the systemic compartment, mucosal tissues contain a large number of IgA producing cells. This immunoglobulin isotype contributes to the protection of exposed mucosal surfaces via a number of mechanisms including prevention of pathogen binding to host cells (epithelial cells and dendritic cells), neutralization of toxins in the lumen, and neutralization of viruses within epithelial cells. Injected vaccines can induce high levels of IgG responses in the bloodstream, but they are not effective at inducing secretory IgA responses which are needed for optimal protection of mucosal surfaces. In contrast with injected vaccines, mucosal vaccines delivered through the oral, rectal, nasal or sublingual routes target Mucosal-Associated Lymphoid Tissues where they can induce innate signals necessary for induction of secretory IgA responses. Despite decades of research on mucosal vaccines, to date, only two oral vaccines and one intranasal vaccine are licensed for use in the US. This proposal will address the overall hypothesis that the adjuvant alum triggers innate signals that restrict the breath of antibody responses and prevent the production of IgA. Our newly generated data suggest that a family of molecules produced by myeloid cells plays a central role in preventing IgA production by alum-based injected vaccines and targeting those molecules will improve protection by increasing IgA production. Aim 1 will focus on the mechanisms underlying innate suppression of IgA responses by myeloid cells in non-mucosal sites. Aim 2 will identify the cells and signaling pathways targeted by pharmacological agents inhibiting this family of molecules to regulate induction of systemic and mucosal immune responses after systemic immunization. Aim 3 will establish whether strategies targeting the innate suppressors of IgA responses promote broad systemic and mucosal immunity and can protect a relevant animal model against infection with an enteric virus.

明矾是目前针对传染原的亚单位疫苗中使用最广泛的佐剂。粘膜组织 代表病原体进入的主要门户。与全身的一般血流相反 粘膜组织中含有大量的 IgA 产生细胞。这种免疫球蛋白同种型 通过多种机制有助于保护暴露的粘膜表面，包括预防 病原体与宿主细胞（上皮细胞和树突状细胞）结合，中和管腔中的毒素，以及 中和上皮细胞内的病毒。注射疫苗可在体内诱导高水平的 IgG 反应 血流，但它们不能有效诱导最佳分泌型 IgA 反应所需的分泌型 IgA 反应。 保护粘膜表面。与注射疫苗相比，粘膜疫苗通过口服、 直肠、鼻腔或舌下途径以粘膜相关淋巴组织为目标，可诱导先天性 诱导分泌型 IgA 反应所必需的信号。尽管对粘膜疫苗进行了数十年的研究， 迄今为止，只有两种口服疫苗和一种鼻内疫苗获准在美国使用。该提案将 解决了佐剂明矾触发限制抗体呼吸的先天信号的总体假设 反应并阻止 IgA 的产生。我们新生成的数据表明，一个分子家族 骨髓细胞产生的 IgA 在防止明矾注射疫苗产生 IgA 方面发挥着核心作用 针对这些分子将通过增加 IgA 的产生来改善保护。目标 1 将重点关注 非粘膜部位的骨髓细胞先天性抑制 IgA 反应的机制。目标2将 识别抑制该分子家族的药物所针对的细胞和信号通路 调节全身免疫后诱导全身和粘膜免疫反应。目标3将 确定针对 IgA 反应先天抑制因子的策略是否促进广泛的系统性和 粘膜免疫，可以保护相关动物模型免受肠道病毒感染。